Cachexia, or disease-associated wasting, is a common occurrence in cancer, renal failure, and infectious disease. This devastating state of malnutrition is brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. The severity of cachexia in many illnesses is the primary determining factor in both quality of life, and in eventual mortality. Other illness induced morbidities including lethargy and loss of reproductive ability also directly compromise the ability of patients to recover from potentially life-saving or extending interventions, including surgery and cytotoxic chemotherapy, and can diminish the motivational drive to aggressively battle the condition. Although cachexia in chronic disease was described more than two thousand years ago, the central mechanisms underlying this disorder of energy homeostasis is poorly understood. Furthermore, there is currently no effective pharmaceutical treatment. The central melanocortin system plays a critical role in regulating feeding behavior, linear growth, metabolic rate, and insulin sensitivity. We have demonstrated that blockade of signaling through the type 4 melanocortin receptor (MC4-R) by genetic and pharmacologic means prevents many of the features of cachexia that would normally occur during acute inflammation in several models of chronic disease. This has led directly to the development of drugs that dampen or block central melanocortin signaling that are currently being tested as therapeutics for cachexia. This proposal is designed to further elucidate the mechanism whereby inflammation leads to excessive activation of central melanocortin signaling. While the primary cytokine signals producing cachexia during illness have been studied in detail, we have limited understanding of the specific hypothalamic cell groups involved in processing these signals. We have shown that cytokines liberated during the disease process activate pro-opiomelanocortin (POMC) neurons by both direct and indirect mechanisms. We have also shown that cytokines affect the function of MCH and orexin neurons, key players in food intake and arousal, respectively. We hypothesize that inflammation alters the function of these neurons and that this in turn will produces various aspects of the illness response including anorexia, decreased movement, elevated basal metabolic rate, lethargy, and alterations in energy partitioning. We further hypothesize that this cellular mechanism represents a final common pathway for the production of cachexia in a variety of chronic disease states, particularly those in which inflammation is known to play an important role.